Ligand discrimination in signaling through an ErbB4 receptor homodimer

The epidermal growth factor (EGF)-like family of growth factors elicits cel lular responses by stimulating the dimerization, autophosphorylation, and t yrosine kinase activities of the ErbB family of receptor tyrosine kinases, Although several different EGF-like ligands are capable of binding to a sin gle ErbB family member, it is generally thought that the biological and bio chemical responses of a single receptor dimer to different ligands are indi stinguishable. To test whether an ErbB receptor dimer is capable of discrim inating among ligands we have examined the effect of four EGF-like growth f actors on signaling through the ErbB4 receptor homodimer in CEM/HER4 cells, a transfected human T cell line ectopically expressing ErbB4 in an ErbB-nu ll background. Despite stimulating similar levels of gross receptor tyrosin e phosphorylation, the EGF-like growth factors betacellulin, neuregulin-1 b eta, neuregulin-2 beta, and neuregulin-3 exhibited different biological pot encies in a cellular growth assay. Moreover, the different ligands induced different patterns of recruitment of intracellular signaling proteins to th e activated receptor and induced differential usage of intracellular kinase signaling cascades. Finally, two-dimensional phosphopeptide mapping of lig and-stimulated ErbB4 revealed that the different growth factors induce diff erent patterns of receptor tyrosine phosphorylation, These results indicate that ErbB4 activation by growth factors is not generic and suggest that in dividual ErbB receptors can discriminate between different EGF-like ligands within the context of a single receptor dimer. More generally, our observa tions significantly modify our understanding of signaling through receptor tyrosine kinases and point to a number of possible models for ligand-mediat ed signal diversification.